Carpal and tarsal tunnel syndromes are painful, progressive conditions caused by compression of a key nerve in the wrist or ankle, respectively. Carpal tunnel syndrome occurs when the median nerve, which runs from the forearm into the hand, becomes pressed or squeezed at the wrist. Tarsal tunnel syndrome occurs when the posterior tibial nerve, which runs from the leg to the ankle, where it divides into the medial and lateral plantar nerves, becomes compressed. Non-steroidal anti-inflammatory drugs, such as aspirin, ibuprofen, and other nonprescription pain relievers, may ease pain. Cool (ice) packs and prednisone (taken orally) or lidocaine (injected directly into the wrist or ankle) can relieve swelling and pressure on the nerve and provide immediate but temporary relief. A doctor may treat the condition with a corticosteroid to decrease inflammation, thus relieving pressure on the nerve. In persistent or severe cases, surgery may be necessary to decompress the tunnel.
Inflammation can be an acute response to trauma or a chronic response to the presence of inflammatory agents. When tissues are damaged, TNF-a attaches to cells to cause them to release other cytokines that cause inflammation. The purpose of the inflammatory cascade is to promote healing of the damaged tissue, but once the tissue is healed the inflammatory process does not necessarily end. Left unchecked, this can lead to degradation of surrounding tissues and associated chronic pain. Thus, pain can become a disease state in itself. That is, when this pathway is activated, inflammation and pain ensue. Often a vicious and seemingly endless cycle of insult, inflammation, and pain sets in. There are numerous examples of conditions in which this cycle is present including, but not limited to, the tendons and soft tissue surrounding and passing through the carpal and tarsal tunnels.
The carpal tunnel is located in the wrist and is surrounded by bone and a fibrous band of tissue, the flexor retinaculum. The median nerve passes through the carpal tunnel along with several flexor tendons. Pain associated with carpal tunnel syndrome results from compression of the median nerve, which may be caused by, inter alia, inflammation of the flexor tendons or swelling of the soft tissue in or around the tunnel. In addition to discomfort, inhibited sensation, and pain, persons suffering from carpal tunnel syndrome frequently have reduced flexibility and range of motion in the wrist.
The tarsal tunnel is located at the medial side of the ankle and is surrounded by bone and the flexor retinaculum. The posterior tibial nerve, which divides into the medial and lateral plantar nerves, passes through the tarsal tunnel along with several flexor tendons, the posterior tibialis artery, and two accompanying veins. The tibial nerve most commonly divides into the medial and lateral plantar nerves while in the tarsal tunnel; however, the tibial nerve divides proximal to the entrance of the tunnel in about five percent of individuals. For purposes of this specification, discussion of the tibial nerve includes the medial and lateral plantar nerves in cases where division occurs proximal to or in the tarsal tunnel. Similar to carpal tunnel syndrome, the pain associated with tarsal tunnel syndrome may result from, inter alia, inflammation of the flexor tendons or surrounding soft tissue. In addition to the tarsal tunnel, compression in the calcaneal tunnel, medial plantar tunnel, and lateral plantar tunnel also contribute to the symptoms of tarsal tunnel syndrome. For the purposes of this specification, any discussion of the tarsal tunnel or the region at or adjacent to the tarsal tunnel includes the calcaneal, medial plantar, and lateral plantar tunnels.
As mentioned above, inflammation of tendons in the carpal and tarsal tunnels are one cause of the syndromes. A normal tendon connects muscle to bone and allows transmission of forces generated by the muscle to the bone, causing joint movement. Tendons are hierarchical structures comprised of longitudinally oriented collagen fibers, which are clustered within a microfibril, which in turn are clustered to form subfibrils, fibrils, fascicles, and finally the tendon. Each level of microanatomy has a similar overall structure of fibers within an extracellular proteoglycan matrix with a paucity of cells dominated by fibroblasts. Cells are present between collagen fibers, and, at the fascicle level of microanatomy, a loose connective tissue invests itself between fascicles and is termed the endotenon, which permits longitudinal movement of fascicles and allows room for blood vessels, lymphatics, and nerves. The epitenon, a loose connective-tissue sheath containing the vascular, lymphatic and nerve supply to the tendon covers the whole tendon and extends deep within the endotenon. The epitenon, is surrounded by paratenon and an inner lining of synovial cells. During an injury to the tendon, damaged cells within the tendon don't have time to recuperate. The cells are unable to repair themselves, causing a chain reaction and leading to tendonitis. When this happens in the tendon, inflammation, or even a rupture of the tendon, may occur. This is common in sport or work activities that require frequent and repeated use of the arm, especially when the arm motions are performed overhead. Degeneration in a tendon causes a loss of the normal arrangement of the collagen fibers that join together to form the tendon. Some of the individual strands of the tendon become weakened due to the degeneration, other fibers break, and the tendon loses strength. See G. Riley, The pathogenesis of tendinopathy. A molecular perspective, Rheumatology, 2004; 43:131-142 (July 2003).
Inflammation is believed to affect disease progression and pain in carpal and tarsal tunnel syndrome. Inflammation can stimulate angiogenesis, and angiogenesis was believed to facilitate inflammation. Inflammation sensitizes nerves, leading to increased pain. Inhibition of inflammation and angiogenesis may provide effective therapeutics for the treatment of osteoarthritis by improving symptoms and retarding joint damage. See C. S. Bonnet et al., Rheumatology, Oxford Journals, 2005; 44:7-16.
Inflammation is recognized to be a key event in the development of normal cartilage and bone. By promoting the delivery of nutrients, oxygen, and cells, blood vessels help maintain the structural and functional integrity of joints and soft tissue and may facilitate tissue repair and healing. The identification of pro-angiogenic mediators, such as vascular endothelial growth factor, has led to the development of anti-angiogenic therapies for the treatment of neoplastic diseases. While not being bound by any theory, the important role of angiogenesis in the pathogenesis of joint disorders, such as rheumatodial arthritis, led to the suggestion that anti-angiogenic therapy may be a useful adjunct to existing approaches in the treatment of rheumatodial arthritis. See Ballara S. C. et al., Int. J. Exp. Pathol., 1999, October; 80 (5):235-50.
It is therefore desirable to provide improved methods of treating carpal and tarsal tunnel syndrome that avoid the drawbacks of the prior art. Specifically, rather than using corticosteroids, it is possible to treat the inflammatory response with anti-cytokine agents such as TNF-a inhibitors, IL-inhibitors, IL-6 inhibitors, IL-8 inhibitors, IL-12 inhibitors, IL-10, autologous blood-derived products (i.e., Orthokine), NF-κB inhibitors, Interferon-gamma (IFN-gamma), etc.